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Autoreactivity to myeloperoxidase (MPO) causes anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), with rapidly progressive glomerulonephritis. Here, we show that a Staphylococcus aureus peptide, homologous to an immunodominant MPO T-cell epitope (MPO409-428), can induce anti-MPO autoimmunity. The peptide (6PGD391-410) is part of a plasmid-encoded 6-phosphogluconate dehydrogenase found in some S. aureus strains. It induces anti-MPO T-cell autoimmunity and MPO-ANCA in mice, whereas related sequences do not. Mice immunized with 6PGD391-410, or with S. aureus containing a plasmid expressing 6PGD391-410, develop glomerulonephritis when MPO is deposited in glomeruli. The peptide induces anti-MPO autoreactivity in the context of three MHC class II allomorphs. Furthermore, we show that 6PGD391-410 is immunogenic in humans, as healthy human and AAV patient sera contain anti-6PGD and anti-6PGD391-410 antibodies. Therefore, our results support the idea that bacterial plasmids might have a function in autoimmune disease.Copyright © 2019, The Author(s).

Autoreactivity to myeloperoxidase (MPO) causes anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), with rapidly progressive glomerulonephritis. Here, we show that a Staphylococcus aureus peptide, homologous to an immunodominant MPO T-cell epitope (MPO409-428), can induce anti-MPO autoimmunity. The peptide (6PGD391-410) is part of a plasmid-encoded 6-phosphogluconate dehydrogenase found in some S. aureus strains. It induces anti-MPO T-cell autoimmunity and MPO-ANCA in mice, whereas related sequences do not. Mice immunized with 6PGD391-410, or with S. aureus containing a plasmid expressing 6PGD391-410, develop glomerulonephritis when MPO is deposited in glomeruli. The peptide induces anti-MPO autoreactivity in the context of three MHC class II allomorphs. Furthermore, we show that 6PGD391-410 is immunogenic in humans, as healthy human and AAV patient sera contain anti-6PGD and anti-6PGD391-410 antibodies. Therefore, our results support the idea that bacterial plasmids might have a function in autoimmune disease.

Neisseria gonorrhoeae causes the sexually transmitted disease gonorrhoea by evading innate immunity. Colonizing the mucosa of the reproductive tract depends on the bacterial outer membrane porin, PorB, which is essential for ion and nutrient uptake. PorB is also targeted to host mitochondria and regulates apoptosis pathways to promote infections. How PorB traffics from the outer membrane of N. gonorrhoeae to mitochondria and whether it modulates innate immune cells, such as macrophages, remains unclear. Here, we show that N. gonorrhoeae secretes PorB via outer membrane vesicles (OMVs). Purified OMVs contained primarily outer membrane proteins including oligomeric PorB. The porin was targeted to mitochondria of macrophages after exposure to purified OMVs and wild type N. gonorrhoeae. This was associated with loss of mitochondrial membrane potential, release of cytochrome c, activation of apoptotic caspases and cell death in a time-dependent manner. Consistent with this, OMV-induced macrophage death was prevented with the pan-caspase inhibitor, Q-VD-PH. This shows that N. gonorrhoeae utilizes OMVs to target PorB to mitochondria and to induce apoptosis in macrophages, thus affecting innate immunity.

Objectives: In microscopic polyangiitis, autoreactivity to myeloperoxidase (MPO) can cause rapidly progressive glomerulonephritis. While it is unknown how tolerance to MPO is lost, infections have been implicated in the development of autoimmunity and disease. MPO409-428 is a promiscuous MPO CD4+ T-cell epitope overlapping a pathogenic B cell MPO epitope. This study tests the hypothesis that molecular mimicry can induce pathogenic anti-MPO autoimmunity. Method(s): BLAST searches were used to identify candidate microbial peptides with homology to MPO409-428. Anti-MPO T-cell responses were determined by immunizing C57BL/6 mice with candidate peptides, then measuring recall responses to MPO by 3[H]-T proliferation and IFN-g and IL-17A ELISPOTs. Anti-MPO antibodies were measured by ELISA, indirect immunofluorescence, and their activity by ex vivo ROS production and by neutrophil glomerular recruitment after passive antibody transfer. Disease was induced by immunizing mice with peptide or whole bacteria, followed by depositing MPO in the glomerulus using low-dose sheep anti-mouse basement membrane globulin. Result(s): Immunizing C57BL/6 mice with 4 different peptides from human pathogens most homologous to the core residues of MPO409-428 did not trigger autoreactivity to MPO or MPO409-428. However, immunization with a peptide derived from 6-phosphogluconate dehydrogenase (mimic-6-pgd), found only in some strains of Staphylococci, did induce T cell autoreactivity to MPO. The corresponding mammalian and closely related bacterial 6-pgd sequences did not induce anti-MPO autoimmunity, demonstrating the specificity of this sequence. Mimic-6-pgd peptide immunization induced MPOANCA that stained neutrophils in a p-ANCA pattern and were functionally active in vitro and in vivo. Mimic-6-pgd-induced MPO T cell autoreactivity resulted in anti-MPO glomerulonephritis in a T cell mediated model. Furthermore, when MPO was planted in glomeruli, mice immunized with whole killed Staphyloco

Microscopic polyangiitis is a small-vessel vasculitic autoimmune disease whereby autoreactivity to the neutrophil enzyme myeloperoxidase (MPO) causes rapidly progressive glomerulonephritis. It is unknown how tolerance is lost, but there are reports in patients that S aureus infections precede anti- MPO autoimmunity, and in other forms of vasculitis, molecular mimicry has been shown to induce cross-reactive pathogenic autoimmunity. This study tests the hypothesis that molecular mimicry induces cross-reactive pathogenic anti-MPO autoimmunity. A BLAST search was used to identify 5 candidate microbial peptides with homology to the immunodominant MPO T-cell epitope, MPO409-428. Anti-MPO T-cell responses were determined by immunizing C57BL/6 mice with candidate peptides then measuring recall responses ex vivo to MPO by 3 [H]-T proliferation and IFN-gamma and IL-17 ELISPOTs. Anti-MPO antibodies were measured by ELISA, immunofluorescence on ethanol-fixed neutrophils and by enumerating neutrophil glomerular recruitment after passive transfer of antibody. Disease was assessed by immunizing mice with peptide or whole bacteria followed by depositing MPO in the glomerulus using low-dose sheep anti-mouse glomerular basement membrane antibodies, then measuring functional and histological endpoints. Only 1 peptide induced cross-reactive T-cell responses to MPO. This peptide was derived from a S aureus plasmid. Antibodies from mice immunized with this peptide cross-reacted with MPO, bound to neutrophils in a perinuclear fashion, and induced neutrophil glomerular recruitment. Furthermore, mice immunized with either this peptide or a clinical strain of S aureus containing the plasmid, developed albuminuria and focal necrotizing glomerulonephritis. This shows that molecular mimicry by a S aureus plasmid derived peptide induces anti-MPO pathogenic autoimmunity.

A new configuration of hydraulic hybrid vehicle (HHV) was presented, which mainly consists of an engine, high-pressure accumulator, lower-pressure reservoir and hydraulic transformer (HT) connected to common pressure rail (CPR), and the working principle of hydraulic hybrid vehicle has been described to extend its energy-regenerated potential. Moreover, the mathematical models of the instantaneous pressure ratio of HT and the characteristic parameters of parallel and series accumulator (i. e. effective volume, specific energy, and charge-discharge efficiency) based on lumped parameters method were built, respectively. The simulation and experimental tests of dynamic characteristics of HT and accumulator were done, the result shows that the theoretical analysis was the same as the experimental results by comparing them in the curve trend, and the series accumulator was much superior to parallel accumulator in terms of pulsation damping of hydraulic transformer, that is the simulation results reasonably and appropriately. © 2013 The Korean Society of Automotive Engineers and Springer-Verlag Berlin Heidelberg.

The Mitochondrial Carrier Family (MCF) is a signature group of integral membrane proteins that transport metabolites across the mitochondrial inner membrane in eukaryotes. MCF proteins are characterized by six transmembrane segments that assemble to form a highly-selective channel for metabolite transport. We discovered a novel MCF member, termed Legionellanucleotide carrier Protein (LncP), encoded in the genome of Legionella pneumophila, the causative agent of Legionnaire's disease. LncP was secreted via the bacterial Dot/Icm type IV secretion system into macrophages and assembled in the mitochondrial inner membrane. In a yeast cellular system, LncP induced a dominant-negative phenotype that was rescued by deleting an endogenous ATP carrier. Substrate transport studies on purified LncP reconstituted in liposomes revealed that it catalyzes unidirectional transport and exchange of ATP transport across membranes, thereby supporting a role for LncP as an ATP transporter. A hidden Markov model revealed further MCF proteins in the intracellular pathogens, Legionella longbeachae and Neorickettsia sennetsu, thereby challenging the notion that MCF proteins exist exclusively in eukaryotic organisms.

Recent high-resolution satellite observations of gravity waves in the middle atmosphere have shown correlations with the strength of the stratospheric jet stream, surface topography, and tropical convection. Seasonal variations of wave-induced stratospheric radiance variances are often the manifestations of modulations of these sources and refractive influences. In this paper, we focus on the seasonal climatology of gravity waves observed by the UARS MLS, while also showing some new results from GPS and AMSU instruments. Our analysis is aided by MWFM modeling of mountain waves at high latitudes and CMAP precipitation indices in the subtropics to provide a clearer picture of global gravity wave dynamics., Pub.. in Advances in Space Research, v35, p192501932, 2005.